Tyrosine Kinase Inhibitors Interstitial Pneumonitis: Diagnosis and Management

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Editorial Commentary

Tyrosine kinase inhibitors interstitial pneumonitis: diagnosis and management

Yayi He, Caicun Zhou

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China Correspondence to: Caicun Zhou. Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, China. Email: [email protected].

Submitted Apr 18, 2019. Accepted for publication May 06, 2019. doi: 10.21037/tlcr.2019.05.02 View this article at: http://dx.doi.org/doi: 10.21037/tlcr.2019.05.02

Lung cancer is the most common cancer in the world (1-3). to different types of cytotoxicity. In this process, TKIs In the past 10 years, studies have shown that tyrosine kinase directly injure the endothelium of alveolar capillaries inhibitors (TKIs), such as gefitinib, afatinib, and crizotinib, and/or the pneumocytes. Cytokines are released and provide significant benefits to advanced non-small cell the inflammatory cells are recruited. These cytokines lung cancer (NSCLC) patients (4,5). NSCLC with positive releasing induce the dysfunction of endothelial and epidermal growth factor receptor (EGFR) or anaplastic lung edema (22). It was reported that increasing IL-6 lymphoma kinase (ALK) mutations can achieve longer played an important role in EGFR-TKI-related ILD, and progression-free survival (PFS) and a higher life quality blocking of IL-6 pathway could reduce the incidence of through treatment with TKIs (4,5). ILD during TKI treatment (23). For gefitinib-induced It should be noted that there are some side effects ILD, metformin demonstrated an inhibitory effect, while of TKIs, such as increased alanine aminotransferase EGFR-TKI combined with metformin in treating NSCLC concentrations, hepatic dysfunction, skin rash, diarrhea, etc. patients was shown to reduce drug-related adverse (5-9). Although it is uncommon, drug-induced interstitial reactions (24). lung disease (ILD) is one of the most serious complications Clinical manifestations of ILD are cough, fever, and of TKIs (10-12), and is thus a major concern during acute or subacute dyspnea, and patients with ILD usually EGFR-TKI treatment (11,12). The incidence of ILD is need to be hospitalized. Respiratory failure is common, about 1% in TKI-treated NSCLC patients worldwide; it and its occurrence in one third of cases is fatal. Chest was reported that ILD occurred in about 3.5% of NSCLC computed tomography (CT) is similar to interstitial patients treated with gefitinib in Japan (13). Meanwhile, pneumonitis, while radiographic findings are nonspecific. the frequency of ILD induced by ALK has been reported The histopathology of ILD induced by TKIs is diffuse to be <1% (14-17). alveolar damage. As it is rare that tissues can be acquired There are some high-risk factors for ILD in patients from these patients, diagnosis is often based on clinical and with TKIs: male sex, smoking, and a history of pulmonary radiographic findings (18). fibrosis (18). Interstitial shadow on chest CT has been The following points can assist in the diagnosis of ILD correlated with TKI-related ILD (19), and it was reported induced by TKIs (18): that prior radiotherapy was also a risk factor for ILD (I) Acute or subacute, progressive dyspnea with or (11,12,19,20). Another potential risk factor of TKI-induced without cough and/or fever; ILD is Anti-PD-1 monoclonal antibodies (21). (II) Exclusion of pulmonary infection; The incidence, histopathology, pathophysiology, and (III) Radiographic findings showing bilateral, diffuse, prognosis of TKI-induced ILD remain poorly understood. or patchy interstitial and/or alveolar opacifications The pathogenesis of ILD was reported to be related without evidence of marked progression of lung

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cancer; Clinical Skills Enhancement Program of Three-year Action (IV) Pathologic findings consistent with ILD (if Plan for Promoting Clinical Skills and Clinical Innovation available). in Municipal Hospitals, and Shanghai Shen Kang Hospital If TKI-induced ILD is diagnosed, it is important to give Development Center Clinical Research Plan of SHDC patients symptomatic supportive treatment. As immune (16CR1001A). The fundamental research funds for the disorder may be one of the mechanisms of TKI-induced central universities. ILD, it is often treated with steroids. Discontinuation of TKIs is another critical option, but can pose a clinical Footnote dilemma: some patients may receive the benefits of TKIs before ILD occurs, some patients may have no suitable Conflicts of Interest: The authors have no conflicts of interest alternative, and some patients may suffer severe side effects to declare. if they switch to other treatments. It was reported that TKI could continue to be used with steroids (25). Doctors References need to judge the benefits and risks and closely monitor their patients (26). Some patients can recover from TKI- 1. Camidge DR, Pao W, Sequist LV. Acquired resistance to induced ILD through a reduction of its dosage. This TKIs in solid tumours: learning from lung cancer. Nat Rev might be another potential therapeutic option for treating Clin Oncol 2014;11:473-81. TKI-induced ILD. Doctors need to pay attention to the 2. Politi K, Herbst RS. Lung cancer in the era of precision recurrence of ILD during the time patients are being treated medicine. Clin Cancer Res 2015;21:2213-20. with a reduced TKI dose. Overall, the understanding of the 3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. underlying mechanisms of ILD and strategies to overcome CA Cancer J Clin 2018;68:7-30. TKI-induced ILD is immature, and further investigation is 4. Zhou C, Wu YL, Chen G, et al. Erlotinib versus required in these areas (27). chemotherapy as first-line treatment for patients with In summary, TKIs have heralded a new era in the advanced EGFR mutation-positive non-small-cell lung treatment of cancers, but ILD still remains its most serious cancer (OPTIMAL, CTONG-0802): a multicentre, side effects. Male sex, smoking, history of pulmonary open-label, randomised, phase 3 study. Lancet Oncol fibrosis, history of radiotherapy, and combination with 2011;12:735-42. immune therapy, are the risk factors of TKI-induced ILD. 5. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or Platinum- TKI-induced ILD presents with cough, fever, dyspnea, Pemetrexed in EGFR T790M-Positive Lung Cancer. N and hypoxemia. Should TKI-induced ILD be diagnosed, Engl J Med 2017;376:629-40. symptomatic supportive treatment is important, and 6. Cameron L, Solomon B. New Treatment Options for patients should be treated with steroids which can be used ALK-Rearranged Non-Small Cell Lung Cancer. Curr simultaneously with TKIs. The discontinuation of TKIs can Treat Options Oncol 2015;16:49. be clinically problematic as other treatment options may not 7. Paz-Ares L, Mezger J, Ciuleanu TE, et al. Necitumumab be viable, and doctors should pay close attention to these plus pemetrexed and cisplatin as first-line therapy in patients. The above facts notwithstanding, the mechanisms patients with stage IV non-squamous non-small-cell lung of ILD and strategies to overcome TKI-induced ILD are cancer (INSPIRE): an open-label, randomised, controlled limited, and need continued study focus. phase 3 study. Lancet Oncol 2015;16:328-37. 8. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and Acknowledgments cisplatin alone as first-line therapy in patients with stage Funding: This study was supported in part by a grant from IV squamous non-small-cell lung cancer (SQUIRE): an National Natural Science Foundation of China (81802255), open-label, randomised, controlled phase 3 trial. Lancet Shanghai Pujiang Program (17PJD036) and a grant from Oncol 2015;16:763-74. Shanghai Municipal Commission of Health and Family 9. Zhou C, Wu YL, Chen G, et al. Final overall survival Planning Program (20174Y0131). National Key Research results from a randomised, phase III study of erlotinib & Development Project (2016YFC0902300), Major Disease versus chemotherapy as first-line treatment of EGFR

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Cite this article as: He Y, Zhou C. Tyrosine kinase inhibitors interstitial pneumonitis: diagnosis and management. Transl Lung Cancer Res 2019;8(Suppl 3):S318-S320. doi: 10.21037/ tlcr.2019.05.02